IRAK4Related Pathways

IRAK4Related Product

IRAK4Background

Gene Summary: This IRAK4 gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. IRAK4 is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

General information above from NCBI

Catalytic activity: ATP + a protein = ADP + a phosphoprotein.

Cofactor: Magnesium.

Subunit structure: Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome. Once phosphorylated, IRAK4 dissociates from the receptor complex and then associates with the TNF receptor- associated factor 6 (TRAF6), IRAK1, and PELI1; this intermediate complex is required for subsequent NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B- mediated gene expression. Interacts with IL1RL1.

Subcellular location: Cytoplasm.

Post-translational: Phosphorylated (By similarity).

Involvement in disease: Recurrent isolated invasive pneumococcal disease 1 (IPD1) [MIM:610799]: Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. Note=The disease is caused by mutations affecting the gene represented in this entry. IRAK4 deficiency (IRAK4D) [MIM:607676]: Causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children. Note=The disease is caused by mutations affecting the gene represented in this entry.

Interleukin-1 receptor-associated kinase 4, also known as Renal carcinoma antigen NY-REN-64, IRAK-4 and IRAK4, is a member of the protein kinase superfamily, TKL Ser/Thr protein kinase family and Pelle subfamily. IRAK4 contains one death domain and one protein kinase domain. IRAK4 is required for the efficient recruitment of IRAK1 to the IL-1 receptor complex following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization. It also phosphorylates IRAK1. A member of the IL-1 receptor (IL-1R)-associated kinase (IRAK) family, IRAK4, has been shown to play an essential role in Toll-like receptor (TLR)-mediated signaling. IL-1-mediated IRAK4 kinase activity in T cells is essential for induction of IL-23R expression, Th17 differentiation, and autoimmune disease. Pharmacological blocking of IRAK4 kinase activity will retain some levels of host defence, while reducing the levels and duration of inflammatory responses, which should provide beneficial therapies for sepsis and chronic inflammatory diseases. Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) which is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD. Defects in IRAK4 are also the cause of IRAK4 deficiency which causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.

IRAK4Alternative Name

IPD1,IRAK4,IRAK-4,NY-REN-64,REN64, [human]

9330209D03Rik,Irak4,IRAK-4,NY-REN-64,8430405M07Rik, [mouse]

IRAK4Related Studies

Strelow,A. et al., 2003, FEBS Lett. 547 (1-3):157-61.

Kim,T.W. et al., 2007, J Exp Med. 204 (5):1025-36.

Trumstedt,C. et al., 2007, J Leukoc Biol. 81 (6):1591-8.

Li,X. et al., 2008, Eur J Immunol. 38 (3):614-8.

Staschke,K.A. et al., 2009, J Immunol. 183 (1): 568-77.

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